CDC25B、Aurora-A在非小细胞肺癌中的表达和临床意义
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摘要
背景:近年来,CDK1的上游磷酸酶CDC25倍受关注。CDC25家族成员CDC25B能在细胞周期关键转换点使CDK脱磷酸化而激活,是早期有丝分裂的启动因子。Aurora激酶家族是新近发现与细胞有丝分裂密切相关的基因,是调节中心体、微管功能的丝/苏氨酸激酶。Aurora-A激酶的活性是CDK1-cyclinB在中心体的募集反应中必须的,而CDC25B的磷酸化是通过Aurora-A激酶完成的。研究发现两者均在多种恶性肿瘤中高表达。
目的:探讨CDC25B、Aurora-A与肺癌发生、发展的关系,旨在寻找肺癌新的分子治疗靶点和肿瘤标志物,为指导肺癌个性化治疗提供一种新的办法。
方法:采用SP法检测76例肺癌组织,11例肺良性病变组织中CDC25B、AuroraA的表达情况与肺癌临床病理参数之间的关系。采用RT-PCR及Western-blot方法检测Aurora A和CDC25BmRNA和蛋白表达。
结果:免疫组化研究结果发现CDC25B、Aurora-A在76例非小细胞肺癌组织与11例肺良性病变组织中的阳性表达率分别是56. 9 %,64.6%和18. 2 %,22.4% ,两者比较差异均有统计学意义( P < 0. 01)。Western bolt检测结果与免疫组化检测Aurora-A、CDC25B蛋白表达结果趋于一致。RT-PCR检测30例非小细胞肺癌组织标本中Aurora-A mRNA和CDC25B mRNA表达水平高于相应癌旁组织,分别为63.3%和56.7%,癌组织与癌旁组织相比较差异有统计学意义(P < 0. 05)。
结论:Aurora-A和CDC25B基因在临床非小细胞肺癌的标本中,都存在mRNA与蛋白水平的高表达。Aurora-A和CDC25B高表达有高度一致性。Aurora-A和CDC25B可能为判断非小细胞肺癌预后的有效指标。
Background: Recently CDC25 family, which is the upstream phosphatase of CDK1 is significantly noticed by many scientists. The CDC25B phosphatases are involved in the dephosphorylation and activation of CDK-1 at the key cell cycle transitions. CDC25B acts as an initiator of the early mitotic events. Aurora-A, as a member found in recent years belonging to serine/threonine kinase family, proves relating to centresomes’maturation and chromosomes division. It has been confirmed as a new oncogene due to its high expression in multiple cancers cells, playing a key role in the normal process of mitosis as proved in previous researches. Aurora-A activity is required for the recruitment of CDK1-cyclin B1 to the centrosome prior to its activation and thecommitment of the cell to mitosis. CDC25B phosphorylation is dependent on Aurora-A. Recent researches found that Aurora-A and CDC25B over expresses in various malignancies.
Objective: To explore the relationship between the expression of CDC25B or Aurora-A and the clinic pathological features of no small cell lung cancer. Provide a theoretical basis for screening tumor marker and molecular therapeutic target of lung cancer.
Methods: Using SP immunohistochemistry methods, the expression of CDC25B and Aurora-A in 76 cases of non small cell lung cancer and 11 cases of benign lung disease was detected. The relationship between the expression of CDC25B or Aurora-A and the clinic pathological features of non small cell lung cancer was analyzed by the statistical method. Aurora A and CDC25B mRNA and protein expression were examined by reverse transcription–polymerase chain reaction (RT-PCR) and Western blot respectively.
Results: In this research, over expression of CDC25B was found in 43/76 patients (56.9%) compared with their corresponding neighboring tissue (2/11, 18.2 %) through immunohistochemistry. Over expression of Aurora-A is 64.6% and 22.4% .with significant difference shown byχ2 test under SPSS 11.5(p﹤0.01). Implying the accordance in Aurora-A or CDC25B protein expression level between the result a from Western bolt and that from immunohistochemistry. In this research, the expression of Aurora-A and CDC25B in tumor in vivo from 30 cases of lung cancer patients was detected through RT-PCR. Over expression was observed in 19 cases (63.3%) /in 17 cases (56.7%) compared with corresponding neighboring tissues. as proven by Bandleader Analysis and Paired t-test under SPSS 11.5(p﹤0.05).
Conclusions: Over expression of Aurora-A and CDC25B mRNA/protein is presents in vitro of non small cell lung cancer. Furthermore the over expression of Aurora-A and CDC25B is compact correlation. And both Aurora-A and CDC25B are all useful factors in predicting prognosis of patients with non small cell lung cancer.
目的:探讨CDC25B、Aurora-A与肺癌发生、发展的关系,旨在寻找肺癌新的分子治疗靶点和肿瘤标志物,为指导肺癌个性化治疗提供一种新的办法。
方法:采用SP法检测76例肺癌组织,11例肺良性病变组织中CDC25B、AuroraA的表达情况与肺癌临床病理参数之间的关系。采用RT-PCR及Western-blot方法检测Aurora A和CDC25BmRNA和蛋白表达。
结果:免疫组化研究结果发现CDC25B、Aurora-A在76例非小细胞肺癌组织与11例肺良性病变组织中的阳性表达率分别是56. 9 %,64.6%和18. 2 %,22.4% ,两者比较差异均有统计学意义( P < 0. 01)。Western bolt检测结果与免疫组化检测Aurora-A、CDC25B蛋白表达结果趋于一致。RT-PCR检测30例非小细胞肺癌组织标本中Aurora-A mRNA和CDC25B mRNA表达水平高于相应癌旁组织,分别为63.3%和56.7%,癌组织与癌旁组织相比较差异有统计学意义(P < 0. 05)。
结论:Aurora-A和CDC25B基因在临床非小细胞肺癌的标本中,都存在mRNA与蛋白水平的高表达。Aurora-A和CDC25B高表达有高度一致性。Aurora-A和CDC25B可能为判断非小细胞肺癌预后的有效指标。
Background: Recently CDC25 family, which is the upstream phosphatase of CDK1 is significantly noticed by many scientists. The CDC25B phosphatases are involved in the dephosphorylation and activation of CDK-1 at the key cell cycle transitions. CDC25B acts as an initiator of the early mitotic events. Aurora-A, as a member found in recent years belonging to serine/threonine kinase family, proves relating to centresomes’maturation and chromosomes division. It has been confirmed as a new oncogene due to its high expression in multiple cancers cells, playing a key role in the normal process of mitosis as proved in previous researches. Aurora-A activity is required for the recruitment of CDK1-cyclin B1 to the centrosome prior to its activation and thecommitment of the cell to mitosis. CDC25B phosphorylation is dependent on Aurora-A. Recent researches found that Aurora-A and CDC25B over expresses in various malignancies.
Objective: To explore the relationship between the expression of CDC25B or Aurora-A and the clinic pathological features of no small cell lung cancer. Provide a theoretical basis for screening tumor marker and molecular therapeutic target of lung cancer.
Methods: Using SP immunohistochemistry methods, the expression of CDC25B and Aurora-A in 76 cases of non small cell lung cancer and 11 cases of benign lung disease was detected. The relationship between the expression of CDC25B or Aurora-A and the clinic pathological features of non small cell lung cancer was analyzed by the statistical method. Aurora A and CDC25B mRNA and protein expression were examined by reverse transcription–polymerase chain reaction (RT-PCR) and Western blot respectively.
Results: In this research, over expression of CDC25B was found in 43/76 patients (56.9%) compared with their corresponding neighboring tissue (2/11, 18.2 %) through immunohistochemistry. Over expression of Aurora-A is 64.6% and 22.4% .with significant difference shown byχ2 test under SPSS 11.5(p﹤0.01). Implying the accordance in Aurora-A or CDC25B protein expression level between the result a from Western bolt and that from immunohistochemistry. In this research, the expression of Aurora-A and CDC25B in tumor in vivo from 30 cases of lung cancer patients was detected through RT-PCR. Over expression was observed in 19 cases (63.3%) /in 17 cases (56.7%) compared with corresponding neighboring tissues. as proven by Bandleader Analysis and Paired t-test under SPSS 11.5(p﹤0.05).
Conclusions: Over expression of Aurora-A and CDC25B mRNA/protein is presents in vitro of non small cell lung cancer. Furthermore the over expression of Aurora-A and CDC25B is compact correlation. And both Aurora-A and CDC25B are all useful factors in predicting prognosis of patients with non small cell lung cancer.
引文
[1]Russell P, Nurse P. CDC25+ functions as an inducer in the mitotic control of fission yeast. Cell, 1986, 45(1):145-153.
[2]Orchard CB, Siciliano I, Sorrell DA,et al. Tobacco BY-2 cells expressing fission yeast CDC25 bypass a G2/M block on the cell cycle.The plant Journal ,2005,44(2):290-299.
[3]Kramer A, Mailand N, Lukas C, et al. Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase.Nat. Cell Biol, 2004,6(9):884–891.
[4]Lincoln AJ,Wickramasinghe D, Stein P, et al. CDC25B phosphatase is required for resumption of meiosis during oocyte maturation.Nat Genet, 2002,30(4):446-449.
[5]Nishioka K, Doki Y, Shiozaki H, et al. Clinical significance of CDC25A and CDC25B expression in squamous cell carcinomas of the oesophagus.Br J Cancer, 2001, 85(3):412-421
[6] Hernandez S, Bessa X, Bea S, et al. Differential expression of CDC25 cell-cycle activating phosphatases in human colorectal carcinoma. Lab Invest Apr,2001, 81(2):465 -473.
[7]Guo J, Kleeff J, Li J, et al. Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma. Oncogene, 2004, 23 (1):71-81.
[8]黄庆先,王国斌,孙念峰,等。CDC25B在胰腺癌中的表达及其临床意义[J].中华实验外科杂志, 2006,23(1): 24-25.
[9] Sasaki H, Yukiue H, Kobayashi Y,et al. Expression of the CDC25B gene as a prognosis marker in non-small cell lung cancer. Cancer Lett, 2001, 173(2): 187-192.
[10]Nagata A, Igarashi M, Jinno S, et al. An additional homolog of the fission yeast CDC25 + gene occurs in humans and is highly expressed in some cancer cells. New Biol,1991,3 (10):959-968.
[11]Gasparotto D, Maestro R, Piccinin S, et al. Overexpression of CDC25A and CDC25B in head and neck cancers. Cancer Res, 1997, 57(12):2366-2368.
[12]Takemasa I,Yamamoto H,Sekimoto M, et al. Overexpression of CDC25B phosphatase as a novel marker of poor prognosis of human colorectal carcinoma.Cancer Res,2000,60(11): 3043-3050.
[13]刘光军,张丹,张力,等。CDC25B在大肠肿瘤中的表达及意.世界华人消化杂志, 2004, 12(5): 1057-1060.
[14] Glover DM, Leibowitz MH, McLean DA, et al. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell, 1995, 81(1):95–105.
[15] Tsai MY, Wiese C, Cao K, et al. A Ran signalling pathway mediated by the mitotic kinase Aurora A in spindle assembly. Nat Cell Biol, 2003, 5(3): 242–248.
[16] Tsai MY, Zheng Y. Aurora A kinase-coated beads function as microtubule-organizing centers and enhance RanGTP-induced spindle assembly. Curr Biol,2005,15(23):2156-2163.
[17] Berdnik D, Knoblich JA. Drosophila Aurora-A is required for centrosome maturation and actin-dependent asymmetric protein localization during mitosis. Curr Biol, 2002, 12 (8): 640–647.
[18] Dutertre S, Descamps S, Prigent C. On the role of aurora-A in centrosome function. Oncogene, 2002, 21(40):6175–6183.
[19] Marumoto T, Honda S, Hara T, et al. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem , 2003,278(51): 51786–51792
[20] Zhang D, Hirota T, Marumoto T, et al. Cre–loxP-controlled periodic Aurora-A overexpression induces mitotic abnormalities and hyperplasia in mammary glands of mouse models.Oncogene,2004,23(54) : 8720–8730.
[21] Terada Y, Uetake Y, Kuriyama R. Interaction of Aurora-A and centrosomin at the microtubule-nucleating site in Drosophila and mammalian cells. J Cell Biol,2003,162(5): 757–763.
[22] Ke YM. Dou Z, Zhang J,et al. Function and regulation of Aurora/IP11P Kinase Family in cell division. Cell Res, 2003, 13 (2):69-81.
[23] Sch iller, JH Harrington D, Belani CP. et al. Comparison of four chempotherapy Reginens for advanced non-small-cell lung cancer. N Eng1 J Med, 2002, 346:92-98
[24] Sen S , Zhou H , Zhang RD , et al. Amplification/ overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst, 2002, 94 (17): 1320-1329.
[25] Bischoff JR, Anderson L, Zhu Y, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J, 1998, 17 (11): 305223065.
[26] Sakakura C , Hagiwara A , Yasuoka R , et al. Tumour -amplified kinase BTAK is a mplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. Br J Cancer, 2001, 84 (6): 8242831.
[27] Li D , Zhu J, Firozi PF , et al. Overexpression of oncogenic STK15/ BTAK/ Aurora- A kinase in human pancreatic cancer. Clin Cancer Res, 2003, 9 (3): 9912997.
[28]邹丽娟,李国权,宫琳琳等. Aurora A激酶在人类不同肺癌细胞株中的表达.癌症,2005,24(7): 792-795.
[29] Cazales M, Schmitt E, Montembault E, et al. CDC25B phosphorylation by Aurora-A occurs at the G2/M transition and is inhibited by DNA damage.Cell Cycle, 2005 ,4(9):1233-1238.
[30]Gabrielli BG, De Souza CP, Tonks ID, et al. Cytoplasmic accumulation of CDC25B phosphatase in mitosis triggers centrosomal microtubule nucleation in HeLa cells. Cell Sci, 1996, 109(5): 1081-1093.
[31] Dutertre S, Cazales M, Quaranta M, et al. Phosphorylation of CDC25B by Aurora-A at the centrosome contributes to the G2–M transition. J Cell Sci, 2004,117(12):2523-2531
[32] Shields PG, Harris CC. Cancer risk and low-penetrance susceptipility genes in gene enviroment interactions. J Clin Oncol, 2000, 18 (11) :2309 - 2315.
[33]Kumagai A, Dunphy WG. The CDC25 Protein Controls Tyrosine Dephosphorylation of the CDC2 Protein in a cell-free system.Cell, 1991, 64(5):903-914.
[34]Marumoto T, Hirota T, Morisaki T,et al. Roles of aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes to Cells, 2002,7(11):1173–1182.
[35]Dekel N.Cellular,biochemical and moleculr mechanisms regulating oocyte maturation.Molecular and Cellular Endocrinology, 2005,234(1-2):19-25.
[36]Lazo JS, Nemoto K, Pestell KE, et al. Identification of a potent and selective pharmacophore for CDC25 dual specificity phosphatase inhibitors. Mol Pharmacol, 2002, 61(4):720-728.
[37]Lazo JS, Aslan DC, Southwick EC, et al. Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase CDC25. J Med Chem, 2001, 44(24):4042-4049.
[38]Sodeoka M, Sampe R, Kojima S, et al. Synthesis of a tetronic acid library focused on inhibitors of tyrosine and dual-specificity protein phosphatases and its evaluation regarding VHR andCDC25B inhibition.Med Chem, 2001,44(20):3216-3222.
[39] Harrington EA, Bebbington D, Moore J, et al. VX-680, a potent and selective small molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nature Med, 2004, 10(3):262–267.
[40]Lee EC, Frolov A,Li R,et al. Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res. 2006, 66(10):4996-5002.
[1]Russell P, Nurse P. CDC25+ functions as an inducer in the mitotic control of fission yeast. Cell, 1986, 45(1):145-153.
[2]Orchard CB, Siciliano I, Sorrell DA,et al. Tobacco BY-2 cells expressing fission yeast CDC25 bypass a G2/M block on the cell cycle.The plant Journal ,2005,44(2):290-299.
[3]Nagata A, Igarashi M, Jinno S, et al. An additional homolog of the fission yeast CDC25 + gene occurs in humans and is highly expressed in some cancer cells. New Biol,1991,3 (10):959-968.
[4]Kramer A, Mailand N, Lukas C, et al. Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase. Nat. Cell Biol, 2004, 6(9):884–891.
[5]Gasparotto D, Maestro R, Piccinin S, et al. Overexpression of CDC25A and CDC25B in head and neck cancers. Cancer Res, 1997, 57(12):2366-2368.
[6]Gabrielli BG, De Souza CP, Tonks ID, et al. Cytoplasmic accumulation of CDC25B phosphatase in mitosis triggers centrosomal microtubule nucleation in HeLa cells. Cell Sci, 1996, 109(5): 1081-1093.
[7]Hoffmann I, Clarke PR, Marcote MJ, et al. Phosphorylation and activation of human CDC25-C by CDC2-cyclin B and its involvement in the self amplification of MPF at mitosis. EMBO J, 1993,12(1):53-63.
[8]Kumagai A, Dunphy WG. Regulation of the CDC25 protein during the cell cycle in Xenopus extracts. Cell, 1992, 70(1):139-151.
[9]Takemasa I,Yamamoto H,Sekimoto M, et al. Overexpression of CDC25B phosphatase as a novel marker of poor prognosis of human colorectal carcinoma. Cancer Res,2000,60(11): 3043-3050.
[10]Cazales M, Schmitt E, Montembault E, et al.CDC25B phosphorylation by aurora-A occurs at the G2/M transition and is inhibited by DNA damage. Cell Cycle, 2005,4(9):1233-1238.
[11]Lindqvist A, Kallstrom H, Lundgren A, et al.CDC25B cooperates with CDC25A to induce mitosis but has a unique role in activating cyclin B1–Cdk1 at the centrosome. J Cell Biol, 2005, 171(1):35–45.
[12]Kumagai A, Dunphy WG. The CDC25 Protein Controls Tyrosine Dephosphorylation of the CDC2 Protein in a cell-free system.Cell, 1991, 64(5):903-914.
[13]Garner-Hamrick PA, Fisher C.Antisense phosphorothioate oligonucleotides specifically down-regulate CDC25B causing S-phase delay and persistent antiproliferative effects.Cancer,1998, 76(5):720–728.
[14]Mirey G, Chartrain I, Froment C, et al. CDC25B phosporylated by pEg3 localizes to the centrosome and the spindle poles at mitosis.Cell Cycle, 2005,4(6):806-811
[15]Dekel N.Cellular,biochemical and moleculr mechanisms regulating oocyte maturation.Molecular and Cellular Endocrinology, 2005,234(1-2):19-25.
[16]Lincoln AJ, Wickramasinghe D, Stein P, et al. CDC25B phosphatase is required for resumption of meiosis during oocyte maturation.Nat Genet, 2002,30(4):446-449.
[17]Baldin V, Pelpel K, Cazales M, et al. Nuclear Localization of CDC25B1 and Serine 146 Integrity Are Required for Induction of Mitosis. J Biol Chem,2002 ,277(38):35176–35182
[18]Brian C. Duckworth, Jennifer S, et al. G2 arrest in Xenopus oocytes depends on phosphorylation of CDC25 by protein kinase A.Proc Natl Acad Sci USA,2002,99(26): 16794-16799.
[19]张扬,张阳,张杰,等。蛋白激酶A/CDC25B通路在小鼠卵母细胞G2期阻滞中的研究.生殖与避孕,2005,25(4):195-200
[20]Lindqvist A, Kallstrom H, Karlsson Rosenthal C. Characterisation of CDC25B localisation and nuclear export during the cell cycle and in response to stress. J Cell Sci, 2004, 117(21): 4979-4990
[21]Dutertre S, Cazales M, Quaranta M, et al. Phosphorylation of CDC25B by Aurora-A at the centrosome contributes to the G2–M transition.J Cell Sci, 2004,117(12):2523-2531
[22]Nishioka K, Doki Y, Shiozaki H, et al. Clinical significance of CDC25A and CDC25B expression in squamous cell carcinomas of the oesophagus. Br J Cancer, 2001, 85(3):412-421
[23]Sasaki H, Yukiue H, Kobayashi Y,et al. Expression of the CDC25B gene as a prognosis marker in non-small cell lung cancer. Cancer Lett, 2001, 173(2): 187-192
[24]Hernandez S, Bessa X, Bea S, et al. Differential expression of CDC25 cell-cycle activating phosphatases in human colorectal carcinoma.Lab Invest, 2001,81(2):465-473
[25]刘光军,张丹,张力,等。CDC25B在大肠肿瘤中的表达及意义.世界华人消化杂志, 2004, 12(5):1057-1060
[26]黄庆先,王国斌,孙念峰,等。CDC25B在胰腺癌中的表达及其临床意义.中华实验外科杂志, 2006,23(1):24-25
[27]Lazo JS, Nemoto K, Pestell KE, et al. Identification of a potent and selective pharmacophore for CDC25 dual specificity phosphatase inhibitors. Mol Pharmacol, 2002, 61(4):720-728
[28]Lazo JS, Aslan DC, Southwick EC, et al. Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase CDC25. J Med Chem, 2001, 44(24):4042-4049
[29]Sodeoka M, Sampe R, Kojima S, et al. Synthesis of a tetronic acid library focused on inhibitors of tyrosine and dual-specificity protein phosphatases and its evaluation regarding VHR andCDC25B inhibition.Med Chem, 2001,44(20):3216-3222
[30]Guo J, Kleeff J, Li J, et al. Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma. Oncogene, 2004, 23 (1):71-81
[2]Orchard CB, Siciliano I, Sorrell DA,et al. Tobacco BY-2 cells expressing fission yeast CDC25 bypass a G2/M block on the cell cycle.The plant Journal ,2005,44(2):290-299.
[3]Kramer A, Mailand N, Lukas C, et al. Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase.Nat. Cell Biol, 2004,6(9):884–891.
[4]Lincoln AJ,Wickramasinghe D, Stein P, et al. CDC25B phosphatase is required for resumption of meiosis during oocyte maturation.Nat Genet, 2002,30(4):446-449.
[5]Nishioka K, Doki Y, Shiozaki H, et al. Clinical significance of CDC25A and CDC25B expression in squamous cell carcinomas of the oesophagus.Br J Cancer, 2001, 85(3):412-421
[6] Hernandez S, Bessa X, Bea S, et al. Differential expression of CDC25 cell-cycle activating phosphatases in human colorectal carcinoma. Lab Invest Apr,2001, 81(2):465 -473.
[7]Guo J, Kleeff J, Li J, et al. Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma. Oncogene, 2004, 23 (1):71-81.
[8]黄庆先,王国斌,孙念峰,等。CDC25B在胰腺癌中的表达及其临床意义[J].中华实验外科杂志, 2006,23(1): 24-25.
[9] Sasaki H, Yukiue H, Kobayashi Y,et al. Expression of the CDC25B gene as a prognosis marker in non-small cell lung cancer. Cancer Lett, 2001, 173(2): 187-192.
[10]Nagata A, Igarashi M, Jinno S, et al. An additional homolog of the fission yeast CDC25 + gene occurs in humans and is highly expressed in some cancer cells. New Biol,1991,3 (10):959-968.
[11]Gasparotto D, Maestro R, Piccinin S, et al. Overexpression of CDC25A and CDC25B in head and neck cancers. Cancer Res, 1997, 57(12):2366-2368.
[12]Takemasa I,Yamamoto H,Sekimoto M, et al. Overexpression of CDC25B phosphatase as a novel marker of poor prognosis of human colorectal carcinoma.Cancer Res,2000,60(11): 3043-3050.
[13]刘光军,张丹,张力,等。CDC25B在大肠肿瘤中的表达及意.世界华人消化杂志, 2004, 12(5): 1057-1060.
[14] Glover DM, Leibowitz MH, McLean DA, et al. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell, 1995, 81(1):95–105.
[15] Tsai MY, Wiese C, Cao K, et al. A Ran signalling pathway mediated by the mitotic kinase Aurora A in spindle assembly. Nat Cell Biol, 2003, 5(3): 242–248.
[16] Tsai MY, Zheng Y. Aurora A kinase-coated beads function as microtubule-organizing centers and enhance RanGTP-induced spindle assembly. Curr Biol,2005,15(23):2156-2163.
[17] Berdnik D, Knoblich JA. Drosophila Aurora-A is required for centrosome maturation and actin-dependent asymmetric protein localization during mitosis. Curr Biol, 2002, 12 (8): 640–647.
[18] Dutertre S, Descamps S, Prigent C. On the role of aurora-A in centrosome function. Oncogene, 2002, 21(40):6175–6183.
[19] Marumoto T, Honda S, Hara T, et al. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem , 2003,278(51): 51786–51792
[20] Zhang D, Hirota T, Marumoto T, et al. Cre–loxP-controlled periodic Aurora-A overexpression induces mitotic abnormalities and hyperplasia in mammary glands of mouse models.Oncogene,2004,23(54) : 8720–8730.
[21] Terada Y, Uetake Y, Kuriyama R. Interaction of Aurora-A and centrosomin at the microtubule-nucleating site in Drosophila and mammalian cells. J Cell Biol,2003,162(5): 757–763.
[22] Ke YM. Dou Z, Zhang J,et al. Function and regulation of Aurora/IP11P Kinase Family in cell division. Cell Res, 2003, 13 (2):69-81.
[23] Sch iller, JH Harrington D, Belani CP. et al. Comparison of four chempotherapy Reginens for advanced non-small-cell lung cancer. N Eng1 J Med, 2002, 346:92-98
[24] Sen S , Zhou H , Zhang RD , et al. Amplification/ overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst, 2002, 94 (17): 1320-1329.
[25] Bischoff JR, Anderson L, Zhu Y, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J, 1998, 17 (11): 305223065.
[26] Sakakura C , Hagiwara A , Yasuoka R , et al. Tumour -amplified kinase BTAK is a mplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. Br J Cancer, 2001, 84 (6): 8242831.
[27] Li D , Zhu J, Firozi PF , et al. Overexpression of oncogenic STK15/ BTAK/ Aurora- A kinase in human pancreatic cancer. Clin Cancer Res, 2003, 9 (3): 9912997.
[28]邹丽娟,李国权,宫琳琳等. Aurora A激酶在人类不同肺癌细胞株中的表达.癌症,2005,24(7): 792-795.
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